The compound known under the generic name omeprazole is described i.a. in European patent specification 0005129.
Omeprazole is useful for inhibiting gastric acid secretion and has gastric mucosa protective activity in mammals and man. In a more general sense, omeprazole may be used for prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory diseases in mammal and man, including e.g. gastritis, gastric ulcer and duodenal ulcer.
The term "omeprazole" as used in this specification designates the neutral form of the compound, that is the form without a salt forming cation present.
Certain salts of omeprazole are described in European patent specification 0124495. In said patent specification the requirements and importance regarding storage stability of pharmaceutical preparations are emphasized. Salts possessing superior properties with regard i.a. to storage stability are described in the said European patent specification. In EP 0124495; examples 5 and 6 disclose the synthesis of a magnesium salt of omeprazole.
The isolation and purification in full manufacturing scale of the described magnesium omeprazole salts presents one major problem in that magnesium omeprazole salt crystals are very fragile making processes utilising such crystals less attractive in full scale production. Performing the process without crystallization of the magnesium omeprazole gives a product which is less suitable as a pharmaceutical substance.
In order to use the magnesium salt of omeprazole, in this specification denoted magnesium omeprazole, in full manufacturing scale in preparing pharmaceutical formulations primarily for oral administration, such as tablets, it is necessary that said magnesium omeprazole possesses a combination of properties which makes such full scale manufacturing feasible. One object of the present invention is to provide a process for full scale production of magnesium omeprazole. A further object of the present invention is to provide a novel form of the magnesium salt of omeprazole which can be used in full scale manufacturing of pharmaceutical formulations, such as tablets.
The combination of physical properties of the novel magnesium omeprazole product of the present invention with respect to the degree of crystallinity, particle diameter, density, hygroscopicity, water content and content of other solvents are favorable and permit the manufacture of magnesium omeprazole in a form which possesses the desired properties.
The novel form of magnesium omeprazole can also be formulated into other forms for oral administration and other types of administration such as rectal administration. Examples of formulations are tablets, pellets, granules, capsules, suspensions and suppositories.
The invention PA0 It is desirable that the product also exhibits the following properties;
We now provide a novel form of the magnesium salt of omeprazole exhibiting the desired combination of physical properties. This makes full scale production of magnesium omeprazole as well as full scale production of pharmaceutical formulations thereof feasible.
The novel process for the manufacture of magnesium omeprazole also circumvents the above described manufacturing problems and renders possible the recovery and work-up of the magnesium omeprazole substance in traditional chemical process equipment.
It has been found that the following property is significant to obtain such product:
a) Crystalline form, with a degree of crystallinity of not less than 70%, preferably higher than 75% as determined by X-ray powder diffraction
b) Particle size measured as mean mass diameter (MMD) less than 30 .mu.m, preferably less than 20 .mu.m as determined by laser diffraction technique.
c) Density between 1.33 g/cm.sup.3 and 1.35 g/cm.sup.3 as determined by powder pycnometer.
d) Hygroscopicity not exceeding 2% increase of weight upon storage for one month up to 94% relative atmospheric humidity as determined gravimetrically.
e) A content of water of between 5% and 10% by weight as determined by titration according to Karl Fischer.
f) A content of methanol less than 0.1% preferably less than 0.05% by weight as determined by gas chromatography, in case methanol is used as solvent.
In a further aspect, the invention also relates to a process for manufacturing the novel form of magnesium omeprazole. This process is described in more detail below.
The invention relates to all of the aspects given under Field of the invention.
The process for producing the novel form of magnesium omeprazole is characterized by the following consecutive steps
a) treating omeprazole or a salt thereof with magnesium alcoholate in a solution
b) separating inorganic salts from the reaction mixture
c) crystallizing magnesium omeprazole
d) isolating the obtained crystalline magnesium omeprazole and, optionally,
e) purifying and drying the crystalline magnesium omeprazole using conventional methods.
The process for manufacturing the new product can be described in the following way.
A lower alcohol, such as methanol, ethanol, n-propanol or iso-propanol, preferably methanol, is treated in a solution of polar solvents with a weighed amount of magnesium at temperatures between 0.degree. C. and reflux temperature. The temperature should preferably be between 10 and 30.degree. C. After addition of the magnesium to the solution the temperature can, in a second step be raised further to between 0.degree. C. and reflux temperature, preferably 20-50.degree. C. After termination of the reaction the temperature is reduced to 0-40.degree. C., preferably 10-25.degree. C. Omeprazole or a salt of omeprazole is then added to the solution and after termination of the reaction the mixture is cooled to -10.degree. C. to +20.degree. C., preferably -5.degree. C. to +5.degree. C. The solvent is then evaporated to 40-60% of the initial volume, which makes the inorganic salts precipitate. The precipitate is separated from the reaction solution for example by centrifugation or filtration and the solution is heated to 5.degree. C. to 30.degree. C. whereafter the solution is seeded with magnesium omeprazole crystals. An amount of water, which is approximately equal to the volume of the solution, is added to start the crystallization. The solution is cooled to -10 to +20.degree. C., preferably 0-10.degree. C. to complete the crystallization. The crystals are then separated from the mother liquid for example by centrifugation or filtration and washed with polar solvents preferably an aqueous lower alcohol such as aqueous methanol. Finally, the produced crystals are dried preferably under reduced pressure and heating.
The process for manufacturing the new form of magnesium omeprazole differs from the earlier known processes in that the product is recovered after a controlled crystallization step in aqueous alcohol, preferably methanol by, first, separating the inorganic salts from the mother liquour. The crystallinity resulting from this step is, unexpectedly, higher and the product possesses a higher degree of purity and is more stable to decomposition from uptake of moisture. The drying step can be performed without caking. The new process is possible to perform in conventional chemical process equipment and gives a product with a higher yield than the processes hitherto known.
The following detailed Example 1 will serve to more fully illustrate the process for manufacturing magnesium omeprazole in full scale according to the present invention. In FIGS. 1 and 2 sample A is manufactured according to this example.